Mini-symposium: UV imaging - a new approach for in vitro drug dissolution and release testing

Wednesday, May 19, 2010

The Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen

Summary:

Dissolution is frequently the rate-controlling step in drug absorption of poorly soluble drugs. In the commonly used dissolution methods the concentration of dissolved substance is measured in the bulk release media. In principle faster and more detailed studies of drug dissolution may be achieved if the dissolution can be measured at the solid-liquid interface. With UV imaging it is possible to measure the intensity of light passing through an area of a quartz tube as a function of position and time. Thus, UV imaging facilitates quantification of drug substances in solution immediately adjacent to the solid material and recording of concentration gradients (7 µm × 7 µm pixel size). This symposium will highlight applications and discuss the potential of the novel, interesting dissolution imaging technology.

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Pharmaceutical dissolution and UV imaging

Stephen Wren, AstraZeneca, Macclesfield, UK

 Most pharmaceuticals are taken by mouth as solid products such as tablets.  As the pharmaceuticals must be in solution to be absorbed by the body, the process of dissolution is very important. 

Dissolution is a heterogeneous process involving a surface reaction, the generation of a concentrated solution, and the dilution of that solution.  Studies of dissolution date back to the late nineteenth century, and the theoretical models developed stress the importance of the concentration gradient running from the surface of the dissolving solid out into the bulk solution.  The application and verification of the theory has, however, been limited by the lack of simple measurement tools which can determine solution concentration at the microscopic level. Most pharmaceuticals contain a UV chromophore and so the new technique of UV imaging has been developed for the selective measurement of local solution concentration.

This presentation will include results obtained from the use of the ActiPix UV imaging detector to the determination of concentration gradients produced by furosemide dissolving in a low pH medium.  The measured gradients will be compared with the general expectations derived from Convective Diffusion theory.

Surface dissolution imaging: how do experiments match up with theory?

David Goodall, Jim Lenke & Kevin Moon, Paraytec Ltd, York, UK

 In this presentation we will review assumptions made in theoretical treatments which underpin measurements of intrinsic dissolution rates. In flow-though systems (USP method 4), the current approach is based on convective diffusion theory developed originally by Nelson and Shah [1] and elaborated by Missel, Stevens and co-workers [2]. Assumptions in [1] include surface concentration being the bulk solubility, and a linear gradient of velocity away from the surface into the bulk solution.

Using the ActiPix SDI300 surface dissolution imager, injection of a pulse of a sample into the flowing dissolution medium allows direct measurement of time and spatially resolved UV absorbance and hence the velocity of the medium as a function of distance from the surface. Similarly, for dissolution of a pure compound of known absorption coefficient, the concentration close to the surface can be measured directly and comparison made with the expected solubility. The intrinsic dissolution rate is obtained by combining the concentration and velocity profiles.

For some sparingly soluble compounds, e.g. griseofulvin, direct imaging of the region close to the sample surface reveals informative data on the nature of the primary event in the dissolution process. In particular, we test whether dissolution proceeds via detachment of molecular aggregates from the surface rather than direct dissolution into single solvated molecules.

For dissolution of a bovine enamel sample into an acetic acid dissolution medium, in which the calcium ion concentration is visualised through complexation with arsenazo III in the dissolution medium, the observed surface concentration is consistent with dissolution controlled by the buffer capacity of the medium.

[1] K. G. Nelson and A. C. Shah, J. Pharm. Sci., 1985, 64, 610-614. K. C. Nelson and A. C. Shah, J. Pharm. Sci., 1985, 64, 1518-1520.  [2] P. J. Missel,L. E. Stevens and J. W. Mauger, Pharm. Res., 2004, 21, 2300-2306. L. E. Stevens, P. J. Missel‌and A. L. Weiner,Pharm. Dev. Tech., 2008, 13, 135-153.

The use of UV dissolution imaging in the screening of drug solid-state forms

R.T. Forbes & Wendy L. Hulse, School of Pharmacy and Pharmaceutical Innovation Research Group, University of Bradford, UK

This presentation will discuss our preliminary attempts to evaluate the use of the dissolution imager as a means of screening the dissolution behaviour of different solid state forms of a drug. The selection of the appropriate solid-state form of a drug is an important preformulation activity and involves considering amorphous, polymorphic and hydrated forms of each candidate.  Often different salts as well as the free acid or base are considered.  Dissolution behaviour is an important criterion towards the optimization of the physical form of a potential drug.  Examples of differences in the dissolution behaviour of different solid-state forms will be discussed.  The advantages and disadvantages of the technique will also be presented to include appropriate correlation with other methods where possible.

Identifying dissolution problems with UV imaging at the solid-liquid interface to accelerate

product development

Jim Lenke & Pranay Rajgarhia, Paraytec, Ltd, York, UK

 Understanding dissolution performance of novel API compounds, abnormal dissolution, and crystalline forms are continual problems for the analytical scientists in accelerating product development. Using UV surface dissolution imaging to characterize performance of these compounds, scientists can now gain better insight into formulation aspects affecting dissolution. Using both poorly and highly soluble compounds, fundamentals of this novel technology will be evaluated to provide the basis for solving dissolution problems. Conclusions drawn will be applied to actual samples presented as movies to show how product development could rapidly be improved.

Insight into dissolution behaviour of amorphous solids by UV imaging and Raman spectroscopy

Marja Savolainen, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen

 There is an increasing interest towards formulation approaches that can be used to improve the solubility of poorly water soluble drugs such as the use of drugs in an amorphous form. However, due to the unstable nature of amorphous drugs, they tend to crystallize. These phase transformations have an influence on the dissolution behaviour, since even a thin layer of crystalline material on the surface would change the dissolution rate of the drug to that of the crystalline form. UV imaging is a new method that can be used to image the dissolution process. It enables the analysis of the initial stages of dissolution that are commonly lost in traditional dissolution testing. The aim of this study was to use a combination of solid phase analysis using Raman spectroscopy and UV imaging to get an insight into the dissolution process of amorphous drugs.

UV imaging for monitoring single crystal dissolution

Jesper Østergaard, Department of Pharmaceutics and Analytical Chemistry,
Faculty of Pharmaceutical Sciences, University of Copenhagen

The dissolution of lidocaine from a single crystal into stagnant buffer solution was monitored at 254 nm. Lidocaine dissolution occurs predominantly from the end of the needle shaped crystal. An attempt to link the dissolution pattern to crystal properties will be made.

This symposium is organised on behalf of Drug Research Academy, PHARMA by associate professor Jesper Østergaard, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, e-mail: joe(at)farma.ku.dk

Participation is free of charge and is open for attendance by all interested parties. Prior registration is not required.